A rare disease takes a Colombian family far from home

Twins Miranda and Olivia Agudelo (with their parents) traveled from Colombia to Boston for a bone marrow transplant.

It was Sherlock Holmes’ powers of observation and deduction that made him one of the most legendary detective characters of all time. But even he might have had a hard time figuring out what was happening to Colombian twins Olivia and Miranda Agudelo.

But with a lot of medical detective work, both by their doctors at home in Colombia and here in Boston, and a lot of help from people across Dana-Farber/Children’s Hospital Cancer Center (DF/CHCC), the girls are doing well and helping doctors and researchers understand how to make bone marrow transplants safer.

A medical mystery begins…

Their mystery started in February of last year, when they were a little over a year old. “They were doing extremely well,” says their father, Alvaro Agudelo. “No flus, no colds, eating well, everything.”

But then the first problem cropped up. First, the family’s ophthalmologist in Colombia diagnosed both girls with familial exudative vitreoretinopathy, a rare problem with the blood vessels in the back of the eye.

After treatment both in Colombia and the U.S., the family went back home and back to their lives. But then their ophthalmologist noticed that neither girl’s eyes were healing properly, both also had lots of bruises.

“That’s when we found out that the girls had low blood counts across the board,” Agudelo says. “An MRI at our local hospital then revealed that both girls had small cerebellums and calcium deposits in the brain.”

…and unfolds

Telomeres (the green dots capping the blue chromosomes) get shorter as we get older. In children with dyskeratosis congenita, genetic mutations make them get too short too quickly.

Putting the clues together—low blood counts, eye problems, brain anomalies—the doctors came up with a possible diagnosis: dyskeratosis congenita (DC), a rare genetic syndrome affecting many organs. But they weren’t sure; none of them had ever seen a case of DC before.

“Dyskeratosis congenita can be a very confusing disease,” says Suneet Agarwal, MD, PhD, a physician and researcher at DC/CHCC who studies DC. “It’s defined by a combination of three clinical signs: abnormalities in skin pigmentation, oddly shaped fingernails and plaques or discolorations in the mouth.

“The reality,” he continues, “is that patients with DC can present with a whole range of signs and symptoms, in different combinations or at different times from patient to patient. What the majority of patients have in common is mutations in genes related to how cells age.”

At this point, though, the Agudelos knew none of this. “Our doctors told us to send blood samples to labs in the U.S. and U.K. to confirm the diagnosis. In the meantime, we started to research where in the U.S. we might go to get treatment for our daughters.”

Their search eventually led them to Agarwal’s doorstep. “My sister-in-law had studied at Harvard, and her contacts there said to get in touch with Dr. Agarwal,” Alvaro explains. “At the same time, our doctors in Colombia had put us in touch with the U.S. National Institutes of Health, where we were told that there were only four doctors in the country making recent advances in DC. Dr. Agarwal was one of them.”

Nontoxic transplants

Suneet Agarwal, MD, PhD

The connections were coming together at just the right time. The girls’ low blood counts meant they were experiencing bone marrow failure, which affects about 80 percent of patients with DC before age 30. They were already getting transfusions, and needed hematopoietic stem cell (aka bone marrow) transplants.

But transplants in children with DC can be tricky. “There’s been a general sense over the last decade that children with DC have a harder time than usual with transplant conditioning,” Agarwal says. Conditioning is the process of preparing a patient’s body to accept a stem cell transplant by wiping out their existing stem cells with radiation and chemotherapy. The process comes with a lot of toxicity. “We think it’s because the mutations that cause the disease cause other organ problems that make the toxicity worse.”

Many centers, including DF/CHCC, have developed “reduced intensity” conditioning regimens, ones that rely less on chemotherapy and radiation and more on suppressing patients’ immune responses. They’ve been successful enough that, Agarwal notes, DF/CHCC now uses a reduced intensity regimen as the standard regimen for all patients with bone marrow failure.

When the Agudelos called him, however, Agarwal was on the cusp of launching a clinical trial that took the next step: taking chemotherapy and radiation out of the conditioning process altogether, in theory making conditioning much less nontoxic.

Patients #1 and #2

“Within days of sending Dr. Agarwal blood samples from the twins, he confirmed for us that they had a kind of DC called Revesz syndrome,” says Agudelo. “At this point he told us that they would be good candidates for stem cell transplants and that he was about to open his trial. He was up front about the fact that it might not work, but we wanted the best possible treatment for our daughters. We decided to take the chance to provide a better future and buy more time for them.”

While Agarwal got the final approvals to start the trial, the Agudelos worked with their insurance provider in Colombia—who agreed to cover a large portion of the transplant after finding that DF/CHCC was the only place able to properly care for the twins—and International Health Services at Boston Children’s Hospital—which provides interpreter services and help with accommodations for international patients—to make all the necessary arrangements to come to Boston.

Through the conditioning process and all through the transplant, the girls have done amazingly well, just as when they were younger. “They had only a couple of fevers at the start of conditioning, but no major problems,” says Agudelo. “And we had our first sign that good things were happening just 12 days after the transplant.”

“Miranda and Olivia had very, very few problems during conditioning, and their transplanted cells engrafted, or ‘took,’ much more quickly than usual,” says Agarwal, who wants to launch a full service, multidisciplinary clinic for patients with DC. “They’re getting their follow-up care here now, but we were able to discharge them in mid-September—again, very quickly for stem cell transplant patients.”

More than just medicine

The Agudelos know their journey isn’t done yet. The transplant only addresses the twins’ bone marrow failure; it can’t cure their DC, and may not have any effect on the liver and/or lung problems the girls are likely to face down the line.

“A day doesn’t go by that we don’t think about our daughters’ future risks,” Agudelo says. “We want them to have as normal a life as any child can have, and we pray that someone will come up with treatments that could help them and others with DC.

“But for now, we’re just thankful that there was someone out there who was willing to unselfishly donate their bone marrow to give our daughters a better future,” he noted.

The NIH told the Agudelos only four doctors in the US had made recent advances in treating dyskeratosis congenita. Suneet Agarwal was one of them.

Agarwal also knows that Miranda and Olivia have a long road ahead of them. “They’ll need lifelong surveillance and preventive care to make sure their other organs stay healthy,” he says. “But with the transplant we think we’ve taken blood failure and perhaps the risk of blood cancer off the table.”

While Agarwal is working with the family’s doctors in Colombia to transition their overall care back home, Boston will now be a frequent part of the Agudelos’ lives. “We plan to go home around the end of March,” Agudelo explains. “But we’ll be back in Boston every summer for the next 14 years to see how they are doing.”

The family’s reasons for coming back for the long term go beyond just the trial. “The more we spoke with Dr. Agarwal, the more we knew that he really cared about the twins and their health,” Agudelo says. “He and everyone else we have worked with—the nurses, the chaplains, the child life specialists, the staff and families on 6 West [where the Stem Cell Transplantation Program’s inpatient unit is located]—has been very compassionate and supportive both of the girls and of us as parents.”

The Agudelos talk to Dr. Agarwal during a recent checkup. So far the twins are doing well.

The experience has also given the family a new direction in life.

“My wife and I have made a promise to God to start a foundation in Colombia to help children and families with terminal or life-threatening illness,” Agudelo says. “We want to help families back home in situations like ours to feel the same kind of support that we’ve felt here, a sense of safety that you feel as soon as you step in the lobby.”

Learn more about the clinical trial the Agudelo twins took part in on Vector, our science and innovation blog. And to learn more about International Health Services at Boston Children’s, visit bostonchildrens.org/international.